Phosphatase PP2A Promotes T_H17 Cell Differentiation And Related Autoimmune Diseases

Phosphatase PP2A expression level is positively correlated to the clinical severity of systemic lupus erythematosus(SLE)and IL17A cytokine overproduction,indicating a potential role of PP2A in regulating TH17 differentiation and inflammation.By generating a mouse strain with the cell-specific ablation of the catalytic subunit a of PP2A in peripheral mature T cells(PP2A cKO),we provide evidence here that PP2A complex is essential in TH17 differentiation.Hence,PP2A cKO mice exhibited a selective reduction of TH17 cell numbers and an attenuated disease severity in an experimental autoimmune encephalomyelitis(EAE)model.Importantly,PP2A deficiency ablated c-terminal phosphorylation of SMAD2 whereas increased c-terminal phosphorylation of SMAD3.Throμgh binding to and regulating the activity of RORyT,the phosphorylational status changes of these R-SMADs subsequently reduced Il17a transcription.Finally,PP2A inhibitors recapitulated the phenotype of PP2A deficiency,i.e.,inhibiting TH17 differentiation and protecting mice from EAE.Together,the current study proves that phosphatase PP2A is important for TH17 differentiation,and inhibition of PP2A might be a possible therapeutic approach for the controlling of TH17-driven autoimmune diseases.